NM_001378743.1:c.914-2070T>C

Variant names:

• chr16-50773096-T-C
• rs1548989
• NM_001378743.1:c.914-2070T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001378743.1(CYLD):​c.914-2070T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 152,240 control chromosomes in the GnomAD database, including 2,577 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.10 (2577 hom., cov: 32)
• Consequence: CYLD NM_001378743.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0870
• Publications: 0 publications found

Genes affected

CYLD (HGNC:2584): (CYLD lysine 63 deubiquitinase) This gene is encodes a cytoplasmic protein with three cytoskeletal-associated protein-glycine-conserved (CAP-GLY) domains that functions as a deubiquitinating enzyme. Mutations in this gene have been associated with cylindromatosis, multiple familial trichoepithelioma, and Brooke-Spiegler syndrome. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

CYLD Gene-Disease associations (from GenCC):

• Brooke-Spiegler syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial cylindromatosis

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Genomics England PanelApp
• frontotemporal dementia and/or amyotrophic lateral sclerosis 8

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• trichoepithelioma, multiple familial, 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• familial multiple trichoepithelioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.348 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378743.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYLD	NM_001378743.1	MANE Select	c.914-2070T>C		intron	N/A	NP_001365672.1
	CYLD	NM_015247.3		c.914-2070T>C		intron	N/A	NP_056062.1
	CYLD	NM_001042355.2		c.914-3083T>C		intron	N/A	NP_001035814.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYLD	ENST00000427738.8	TSL:5 MANE Select	c.914-2070T>C		intron	N/A	ENSP00000392025.3
	CYLD	ENST00000398568.6	TSL:1	c.914-3083T>C		intron	N/A	ENSP00000381574.2
	CYLD	ENST00000569418.5	TSL:1	c.914-3083T>C		intron	N/A	ENSP00000457576.1

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15465 AN: 152122 Hom.: 2557 Cov.: 32

Gnomad AFR AF: 0.352

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0379

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00269

Gnomad OTH AF: 0.0574

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.102 AC: 15528 AN: 152240 Hom.: 2577 Cov.: 32 AF XY: 0.0975 AC XY: 7262 AN XY: 74450

African (AFR) AF: 0.352 AC: 14615 AN: 41482

American (AMR) AF: 0.0378 AC: 579 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00269 AC: 183 AN: 68020

Other (OTH) AF: 0.0568 AC: 120 AN: 2114

Alfa AF: 0.00416 Hom.: 7

Bravo AF: 0.118

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.0
DANN	Benign	0.52
PhyloP100		0.087
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1548989; hg19: chr16-50807007;